FENBENDAZOLE
First Draft Prepared by
Dr. William C. Keller,
Food and Drug Administration,
Rockville, Maryland USA
1. EXPLANATION
Fenbendazole is a light brownish-gray odourless, tasteless
crystalline powder which is insoluble in water, but highly soluble
in DMSO. It is a broad spectrum veterinary anthelmintic used in
canines, equines, ruminants and swine. Fenbendazole has not been
previously evaluated by the Joint FAO/WHO Expert Committee on Food
Additives.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution, and excretion
Studies were performed to obtain basic information on the
pharmacokinetics of 14C-fenbendazole after single oral doses in
dogs, rats, rabbits, and sheep. The doses used were 5 mg/kg b.w. for
sheep and 10 mg/kg b.w. for the other species. The material tested
was administered as an aqueous suspension in 2% starch mucilage. All
data are based on radioactivity, with metabolism not taken into
account.
Absorption was slow, but more rapid in monogastrics. The
highest concentrations measured in blood were 0.9 µg/ml in rats 5 to
7 hours post-administration, 0.9 µg/ml in rabbits 8 hours
post-administration, 0.4 µg/ml in dogs 24 hours post-administration
and 0.32 µg/ml in sheep 2-3 days post-administration. Elimination
t´ from blood was 6 hours in rats, 13 hours in rabbits, 15 hours
in dogs, and one day in sheep. In all animals except rabbits,
elimination occurred >90% in faeces, with <7% in urine. In
rabbits, excretion was 75% in faeces and 21% urine. At three days
post-administration 98% elimination in dogs, 92% elimination in
rabbits, and 99% elimination in rats had occurred. Hepatic
distribution at 7 days was highest (2.7 ppm) in sheep and lowest
(0.06 ppm) in rats (Kellner & Christ, 1973).
Investigations into the pharmacokinetics of 14C-fenbendazole
after intravenous and oral administration were carried out in the
rat, rabbit, dog, sheep, and pig (oral only). All species received
5 mg/kg b.w. fenbendazole as a 2.5% aqueous suspension in 2% starch
mucilage. All data are based on radioactivity, with metabolism not
taken into account.
The decrease in blood levels after i.v. administration occurred
with a t´ of 10 and 13 hours in the dog, >7 hours in the rat, 12
and 18 hours in the rabbit, and 13 hours in sheep. The decrease in
blood levels after oral administration occurred with a t´ of 15 ±
3 hours in the dog, 6 ± 1 hours in the rat, 13 ± 4 hours in the
rabbit, 9.4 ± 1.1 hours in the pig and 28 ± 4 hours in sheep. The
t´ for monogastrics was similar for oral and i.v. administration,
but for sheep the post-iv elimination was much faster due to lack of
a rumen effect on absorption. Elimination occurred mainly in the
faeces and was nearly complete after one week. Intestinal absorption
was about 70% in the rabbit, 25-50% in the rat, >33% in the pig,
25% in sheep and >20% in the dog. Elimination via the urine during
7 days following i.v. administration was significant: rabbit 38 -
40%, rat 23 ± 5.7%, dog 29 - 38% and sheep 34%. Of this about 90% in
the rat, 69-77% in the dog, 55% in the rabbit, and 45% in the sheep
was eliminated within 24 hours. Urinary elimination in the pig and
sheep following oral administration was 31-36% and 8-11%,
respectively. The largest component of the dose was eliminated in
the faeces by all species. The distribution pattern for fenbendazole
6 - 8 hours after an oral dose in the rabbit, dog, and rat showed
the highest levels in the liver (Villner et al., 1974).
2.1.2 Biotransformation
Sheep and rabbits received 10 mg/kg b.w. 14C-fenbendazole
orally, and faeces and urine were evaluated. About 10-20% of
excretion occurred in urine with the remainder being in faeces.
About 50-75% of the urinary extract occurred as the p-OH metabolite
(Klöpffer, 1973).
A single dose of fenbendazole was administered orally to rats,
rabbits, and dogs, and serum levels of parent compound and of three
metabolites (oxfendazole, oxfendazole sulfone, and p-OH oxfendazole)
were determined post-administration at various times. Rats received
500 mg/kg b.w., while rabbits and dogs received 25 mg/kg b.w. The
detection limit was 0.05 ppm for parent drug and the NH2
metabolite (which was not distinguishable from parent), and 0.01 ppm
for the other metabolites. Blood levels of parent drug were
detectable after 24 hours in all species and in the dog and rat at
48 hours (rabbit blood levels were not evaluated at 48 hours).
Levels of SO and SO2 metabolites were also found, while
practically no traces of the p-OH metabolite were found (Düwel &
Uihlein, 1980).
The disposition and metabolism of fenbendazole were studied
in vivo in cattle, chickens, sheep, goats, rabbits, and in vitro
in hepatic preparations from cattle, sheep, goats, rabbits, rats,
chickens, ducks, turkeys, and catfish. The major urinary metabolite
when fenbendazole was administered either i.v. or orally (5 mg/kg
b.w.) was p-OH fenbendazole. The sulfoxide and sulfone appeared in
plasma but were recovered in only trace amounts in urine or faeces,
and the amine was a minor metabolite appearing only occasionally in
plasma (Short et al., 1988).
A general metabolism scheme may be found on page 23. The ready
interconversion of oxfendazole and fenbendazole is notable. Also
important, in considering the benzimidazoles as a group, is the
entry of febantel to the oxfendazole-fenbendazole pool through
either conversion of febantel to fenbendazole directly or the
conversion of febantel through the sulfoxide to oxfendazole.
2.2 Toxicological studies
2.2.1 Table 1: Acute toxicity studies
Species Sex Route LD50 Reference
(mg/kg b.w.)
Mouse M&F oral > 10 000 Scholz & Schultes,
1973a
Mouse M&F s.c. > 3 200 Scholz & Schultes,
1973a
Mouse M&F i.p. > 3 200 Scholz & Schultes,
1973a
Rat M&F oral > 10 000 Scholz & Schultes,
1973b
Rat M&F s.c. > 2 000 Kramer & Schultes,
1973a
Rat M&F i.p. > 1 250 Kramer & Schultes,
1973b
Rabbit M&F oral > 5 000 Scholz & Schultes,
1973c
Dog M&F oral > 500 Scholz & Schultes,
1973d
Swine M&F oral > 5 000 Duwel, 1974
Sheep F oral > 500 Wilkins, 1973
The oral LD50 of p-OH fenbendazole was >10 000 mg/kg b.w. in
mice and rats (Kramer & Schultes, 1974c,d)
2.2.2 Short-term studies
2.2.2.1 Mice
Fenbendazole was submitted to a general pharmacologic screening
procedure in mice over a dose range of 100 to 300 mg/kg b.w. The
following observations were reported: Increased motor activity
induced by administering the CNS stimulant methamphetamine was not
changed by pretreatment with fenbendazole, pretreatment of mice with
fenbendazole had no influence on hexobarbitone anaesthesia as
measured by sleep time, fenbendazole treatment was found to have no
effect on pain perception using the radiant heat method test,
maximal electroshock convulsions in mice were not affected by
fenbendazole, and fenbendazole had no apparent anticonvulsant
activity against pentamethyletetrazole (Vogel & Alpermann, 1973).
2.2.2.2 Rats
Fenbendazole was submitted to a general pharmacologic screening
procedure in rats over a dose range of 100 to 300 mg/kg b.w. The
following observations were reported: Fenbendazole was determined
not to have anti-inflammatory activity in the rat paw oedema test
using carrageenan as an irritant, there was no change in body
temperature when fenbendazole was administered to yeast-fevered
rats, and fenbendazole was negative for diuretic activity (Vogel &
Alpermann, 1973).
Fenbendazole was administered via stomach tube to groups of 10
male and 10 female immature Wistar rats at the rate of 0, 25, 250,
and 2500 mg/kg b.w./day for 30 days. Food consumption was determined
continuously and body weight twice weekly. Rats were observed daily
and clinically examined weekly. Haematology, clinical chemistry and
urinalysis were determined prior to treatment initiation and at
sacrifice. Half the animals were sacrificed one day after treatment
ceased and the remainder were sacrificed 8 days after treatment
ceased. The rats received a complete gross necropsy, organ weights
were determined, and a standard array of tissues was examined
histopathologically following sacrifice. No treatment-related
findings were reported (Kramer & Schultes, 1973c).
Fenbendazole was administered via stomach tube to groups of 15
male and 15 female immature Wistar rats at the rate of 0, 25, 200,
and 1600 mg/kg b.w./day for 90 days. At treatment day 61 doses for
five male and female rats were increased to 2500 mg/kg b.w./day.
Food intake was determined continuously and body weight twice
weekly. Rats were observed daily and clinically examined weekly.
Haematology, clinical chemistry and urinalysis were determined prior
to treatment initiation, at the sixth week of treatment and at
sacrifice. Ten animals were sacrificed 1 day after treatment ceased
and the remainder were sacrificed 7 days after treatment ceased. The
rats received a complete gross necropsy, organ weights were
determined, and a standard array of tissues was examined
histopathologically following sacrifice. Two rats from the 1600 and
5 rats from the 2500 mg/kg b.w./day groups were observed to have
tremors after the 84th treatment. No other treatment-related
findings were reported (Kramer & Schultes, 1974a).
A 15-week oral toxicity study in Charles River CD rats was
performed to evaluate the toxicity of fenbendazole in rats.
Fenbendazole was provided in the feed to groups of 50 rats/sex
derived from the F1a generation of a 3-generation reproductive
toxicology study at levels to yield a dose of 160, 400, or
1000 mg/kg b.w./day. Animals were observed daily and weights and
food consumption recorded weekly. At 12 weeks clinical chemistry,
haematology, urinalysis, and ophthalmic examinations were conducted.
Rats which died during the study and rats from the 1000 mg/kg
b.w./day and control groups were necropsied.
The treated male groups all gained less weight than controls
but there was a reverse relationship to dose. The treated groups
also weighed less than controls at study initiation: the 1000 mg/kg
b.w./day male mean weight was 75% of controls and the female mean
weight was 73% of controls. No other treatment-related observations
were reported. It should be noted [see Goldenthal 1979b] that this
study was initiated as a 2-year chronic study that was apparently
terminated due to toxicity (Goldenthal, 1979a).
2.2.2.3 Dogs
Fenbendazole was administered to 6-week old puppies to
determine the safety of the 22.2% granules or 10% suspension
formulations. Groups of 3 beagle pups/sex received doses of 0, 50,
or 250 mg/kg b.w./day granules or 250 mg/kg b.w./day suspension
provided in gelatin capsules for 6 days. Clinical signs,
haematology, and clinical chemistry were evaluated. No
treatment-related effects were reported (Mehring, 1982).
Fenbendazole was administered in gelatin capsules to groups of
2 male and 2 female beagles for 30 consecutive days at the rate of
0, 25, 80, or 250 mg/kg/day. The dogs were 7 to 34 months old at
initiation of the experiment. Food consumption was determined daily
and weights were determined weekly. Dogs were observed daily and
examined weekly for treatment-related signs. Haematology, clinical
chemistry, and urinalysis were performed prior to treatment
initiation and at sacrifice. Following sacrifice, dogs received a
gross necropsy and organ weights were determined. A standard
selection of organs was evaluated histopathologically.
Treatment-related lesions reported include lymph follicle
proliferation in the region of the stomach pyloric glands at
250 mg/kg b.w./day and low-grade diffuse cellular centrilobular
fatty degeneration of the liver in males at 80 and 250 mg/kg
b.w./day. The NOEL was 25 mg/kg b.w./day (Kramer & Schultes, 1973d).
Fenbendazole was administered in gelatin capsules to 4 groups
of 3 male and 3 female beagle dogs for 90 consecutive days at the
rate of 0, 20, 50, or 125 mg/kg b.w./day. The dogs were 8 to 48
months old at initiation of the experiment. Food consumption was
determined daily and weights were determined weekly. Dogs were
observed daily and examined weekly for treatment-related signs.
Haematology, clinical chemistry, and urinalysis were performed prior
to treatment initiation, after 30 days of treatment, and at
sacrifice. Following sacrifice, dogs received a gross necropsy and
organ weights were determined. A standard selection of organs was
evaluated histopathologically. The gastric mucosa was reported to
contain lymph follicles and lymphocytic infiltration in both treated
and control dogs. No treatment-related findings were reported
(Kramer & Schultes, 1974b).
The toxicity of fenbendazole was evaluated in beagle dogs by
administering fenbendazole in gelatin capsules to 4 groups of 4 male
(5.5 to 9.7 kg) and 4 female (4.8 to 7.3 kg) dogs at levels of 0,
20, 50, and 125 mg/kg b.w./day for 6 months. Dogs were housed
individually in metal metabolism cages. Food consumption and weights
were determined weekly. Dogs were observed daily and examined weekly
for treatment-related signs. Reflexes were examined prior to
treatment and at 1, 3 and 6 months of treatment. Ophthalmoscopic
examinations, haematology, clinical chemistry, and urinalysis were
performed prior to treatment and at 3 and 6 months. Following
sacrifice dogs received a gross necropsy and organ weights were
determined. A standard selection of organs from the control and
125 mg/kg b.w./day treatment groups were evaluated
histopathologically. In addition, tissues from dogs in the 20 and
50 mg/kg b.w./day groups in which gross lesions were observed or in
which treatment-related lesions were observed in the 125 mg/kg group
were also evaluated histopathologically.
A treatment-related nodular appearance of the gastric mucosa
was observed at gross necropsy in all treated groups but not
controls. Formation of lymphoid nodules in the gastric mucosa
corresponding to this gross lesion was observed on histopathologic
evaluation in all treatment groups. Focal encephalomalacia,
satellitosis and neuronophagia were observed in the cerebra of two
dogs at the 125 mg/kg b.w./day level and slight perivascular
inflammation and gliosis were reported in the cerebrum of another
animal at the 125 mg/kg b.w./day level. Since effects were observed
at the lowest dose of 20 mg/kg b.w./day, there was no NOEL (Wazeter
& Goldenthal, 1977).
The toxicity of fenbendazole was evaluated in beagle dogs by
administering fenbendazole in gelatin capsules to 5 groups of 6 male
(5.9 to 14.1 kg) and 6 female (5.4 to 11.6 kg) dogs at levels of 0,
4, 8, 12, and 20 mg/kg b.w. daily for 6 months. Dogs were housed
individually in metal metabolism cages. Food consumption and weights
were determined weekly. Dogs were observed daily and examined weekly
for treatment-related signs. Reflexes were examined prior to
treatment and at 1, 3 and 6 months of treatment. Ophthalmoscopic
examinations, haematology, clinical chemistry, and urinalysis were
performed prior to treatment and at 3, and 6 months. After 6 months
of treatment 4 dogs of each sex/group were sacrificed while the
remaining 2 dogs of each sex/group were sacrificed 3 weeks after
treatment had ceased. At sacrifice, each dog received a complete
gross necropsy and adrenals, brain, heart, kidneys, liver, spleen,
pituitary, testes, ovaries, and thyroid were weighed. A standard
selection of organs from the control and 20 mg/kg b.w./day treatment
groups were evaluated histopathologically. In addition, tissues from
dogs in the 4, 8, and 12 mg/kg b.w./day groups in which gross
lesions were observed, and mesenteric lymph nodes, stomach, colon,
and testes were also evaluated histopathologically.
An increased number of treated dogs had lymphocytic foci in the
lamina propria of the gastric mucosa compared to control dogs. The
extent of this effect appeared to be dose-related. Very slight to
moderate hyperplasia of mesenteric lymph nodes was also increased in
treated groups. The investigators believed the increased incidence
in treated groups may indicate a treatment-related local irritant
effect. Mesenteric lymph nodes from dogs sacrificed 3 weeks after
cessation of treatment were deemed to have hyperplasia and
congestion (Goldenthal, 1978).
An independent histopathologic review of stomach mucosal tissue
and mesenteric lymph nodes from this and the previous study was
performed. This review concluded that lymphoid hyperplasia of the
gastric mucosa was associated with fenbendazole treatment. The
reviewers were not convinced that this effect was a direct irritant
effect or that the gastric effect was associated with lymph node
hyperplasia. They further stated that any nonspecific irritant could
produce the lymph node changes (Dua, 1981).
Histopathologic changes reported in the two previous studies
occurred in the control as well as the treated dogs. The incidence
occurring at the high doses suggests a treatment-related effect,
however, the incidence of changes occurring in the low-dose group
appears to be within the range of biological variation.
Interpretation of these changes would have been facilitated by
availability of historical control data. Results from this study are
consistent with a NOEL of 4 mg/kg/day. This conclusion is supported
by the following study.
A further 14-week study using 3 beagles/sex/dose was done to
assess the oral toxicity of fenbendazole, particularly effects on
stomach mucosal lymphoid follicles and mesenteric lymph nodes. Dogs
received doses of 0, 1, 2, 5, or 10 mg/kg b.w./day provided in
gelatin capsules. Food consumption was determined daily and weights
were determined weekly. Dogs were observed daily and examined weekly
for treatment-related signs. Haematology, clinical chemistry, and
urinalysis were performed prior to treatment initiation, and at week
13. Following sacrifice, dogs received a gross necropsy and liver,
kidney, and spleen weights were determined. Organs evaluated
histopathologically included liver, kidney, spleen, mesenteric lymph
nodes, samples of the stomach regions and tissues with gross
lesions. No treatment-related findings were reported (Doerr &
Carmines, 1983).
2.2.2.4 Swine
The toxicity of fenbendazole was evaluated by dosing 8 growing
pigs via gavage with 2000 mg fenbendazole/kg b.w./day for 14 days.
The animals were observed daily, and blood and urine samples were
collected on alternate days including baseline values. The pigs were
sacrificed 10 days after the last dose and subjected to complete
gross and histopathologic examination. Four pigs developed pneumonia
during the treatment. Treatment-related leukopenia developed on day
6 of dosing but returned to normal on day 18, 4 days after treatment
ceased. Both the segmented neutrophils and lymphocytes were
affected. Sorbitol dehydrogenase values were significantly increased
from treatment day 4, but returned to baseline on day 20, 6 days
after treatment ceased. No treatment-related gross or
histopathologic lesions were reported (Hayes et al., 1983a).
The toxicity of fenbendazole was evaluated in groups of 5
female pigs in which fenbendazole was provided in feed at the rate
of 0, 25, 75, or 125 mg/kg b.w./day for 5 days. They were observed
daily. Blood and urine samples were collected on days -5, -2, 0, 3,
7, 10 and 15. The pigs were sacrificed 10 days after the last dose
and subjected to complete gross and histopathologic examination.
Leukopenia developed on day 3 for the 75 and 125 mg/kg b.w./day
groups and after treatment ceased, on day 7 in the 25 mg/kg b.w./day
group, but all groups had returned to normal on day 15, 10 days
after treatment ceased. The segmented neutrophils and lymphocytes
were affected. In groups receiving 75 and 125 mg/kg b.w./day,
sorbitol dehydrogenase values were significantly increased from
treatment day 3, but returned to baseline on day 10, 5 days after
treatment ceased. No treatment-related gross or histopathologic
lesions were reported (Hayes et al., 1983b).
Thirty sows were divided into groups receiving 0, 3, 9, 15 and
25 mg fenbendazole/kg b.w./day in feed for 3 days. The animals were
maintained for an additional 10 days after treatment ceased. Blood
and urine were collected on alternate days including during a 10-day
pretreatment phase. Clinical chemistry, haematology, urinalysis and
gross and histopathologic observations revealed no treatment-related
effects. The NOEL was 25 mg/kg b.w./day (Booze & Oehme, 1983).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
The carcinogenicity of fenbendazole was evaluated in Charles
River CD-1 mice. In a 2-year study, 480 six-week old mice were
divided into 4 groups of 60 male and 60 female mice which received
fenbendazole in the diet at levels targeted to provide doses of 0,
45, 135, and 405 mg/kg b.w./day. The test material was mixed with
the diet by adding it to 500 g of food and blending, then mixing
this premix with the mouse diet in a blender. The fenbendazole
concentration was based on the most recent body weight and food
consumption data, and fresh diets were prepared weekly. Samples of
the diet containing the test substance were taken at periodic
intervals during the study. Mice were observed daily for general
physical appearance, behaviour, and toxic signs, and observations
recorded weekly except moribundity/mortality which were recorded
daily. Individual body weights and food consumption were recorded
weekly. After 24 months of fenbendazole administration the surviving
mice were sacrificed and complete necropsies performed. All animals
that died during the course of the study were also necropsied.
Histopathologic evaluation was performed on a standard array of
tissues from the control and high-dose group and all tissues where
lesions were observed at necropsy in all dose groups.
Survival in treated groups was somewhat reduced when compared
with controls: Control: - 55% M and 60% F; 45 mg/kg b.w./day - 43% M
and 37% F; 135 mg/kg b.w./day - 47% M and 42% F; and 405 mg/kg
b.w./day - 37% M and 43% F. Sporadic body weight gain differences
between treatment groups and controls occurred at various times
during the study, but no apparent treatment-related alteration was
observed. Food consumption was comparable for all groups. The
incidence of inflammatory lesions and proliferative lesions was
unrelated to fenbendazole treatment. Total numbers of benign and
malignant neoplasms for the treated group and control were similar.
No compound effect was evident histopathologically. Based on these
results the investigators concluded that no fenbendazole-related
effects were observed in any treatment group during the study
(Goldenthal, 1980b).
2.2.3.2 Rats
The chronic toxicity, including carcinogenicity, of
fenbendazole was evaluated in Charles River CD rats. In a lifetime
study including an in utero phase fenbendazole was provided in the
diet at dose levels of 0, 5, 15, 45, and 135 mg/kg b.w./day. Groups
of 50 male and 50 female rats, derived from a three-generation
reproduction study performed using the same dose-levels (as the
F1a rats) were used in the study. Surviving male rats were
terminated at week 123 and surviving females were terminated at week
125. Febendazole was mixed with the diet. The fenbendazole
concentration was based on the most recent body weight and food
consumption data and fresh diets were prepared weekly. On day 0 and
on day 7 of weeks 1, 14, 52, 104, and 122 samples of the diet
containing the test substance were taken.
Rats were observed daily for general physical appearance,
behaviour, and toxic signs and observations recorded weekly except
moribundity/mortality which were recorded daily. Individual body
weights and food consumption were recorded weekly. Opthalmoscopic
examination was performed at 3, 6, 12, 18, and 24 months and at
termination. Haematology, clinical chemistry, and urinalysis were
performed on samples obtained at 3, 6, 12, 18, and 24 months from 10
rats/sex/dose (selected randomly). The surviving rats were
sacrificed and complete necropsies performed. The following organs
were weighed: adrenals, brain, heart, kidneys, liver, spleen,
testes, and ovaries. All animals that died during the course of the
study were necropsied but no organ weights were taken.
Histopathologic evaluation of a standard array of tissues from the
control and high-dose group, and liver and mesenteric lymph nodes,
and all tissues in which lesions were observed at necropsy in the
other dose groups was performed.
Treatment-related physical signs reported included diarrhoea
and red material in faeces (45 mg/kg b.w./day and 135 mg/kg
b.w./day) and reddish-brown urine (15, 45, and 135 mg/kg b.w./day).
Mortality was not statistically different from controls for any
treatment group. At 80 weeks, survival for all groups exceeded 80%,
except high dose males with 72% survival. At terminal sacrifice,
survival was: Controls: - 34% M and 36% F; 5 mg/kg b.w./day - 42% M
and 28% F; 15 mg/kg b.w./day - 46% M and 38% F; 45 mg/kg b.w./day -
44% M and 36% F; and 135 mg/kg b.w./day - 24% M and 24% F. Body
weights at terminal sacrifice were significantly lower for the 45
and 135 mg/kg b.w./day groups compared with controls. This is
reflective of the weight differences at the beginning of the study.
However, weight gains were also reduced for the 45 and 135 mg/kg
b.w./day groups versus controls. Food consumption was comparable for
all groups. Sporadic significant differences occurred in the
haematologic, clinical chemistry and urinalysis parameters. Of
these, only the alkaline phosphatase in the 15, 45 and 135 mg/kg
b.w./day groups and SGOT in the 135 mg/kg b.w./day group were
consistently elevated in a manner suggesting biological
significance. The following were noted at gross necropsy:
enlargement or cyst formation in lymph nodes of rats from the 45 and
135 mg/kg b.w./day groups, liver mass and/or nodule formation in
rats of the 135 mg/kg b.w./day group, cyst formation in the liver of
females in the 135 mg/kg b.w./day group, and testicular masses among
males at the 135 mg/kg b.w./day dose-level.
Treatment-related histopathologic findings reported included:
sinus ectasia and reactive hyperplasia of the mesenteric lymph nodes
in all but the low dose level; centrilobular hepatocellular
hypertrophy, focal hepatocellular hyperplasia, hepatocellular
cytoplasmic vacuolation, focal bile duct proliferation, and biliary
cyst formation in the 45 and 135 mg/kg b.w./day dose levels, nodular
hepatocellular hyperplasia in female rats of the 45 and 135 mg/kg
b.w./day dose levels, and testicular interstitial cell adenomas in
the 135 mg/kg b.w./day male rats. Based on these findings the
authors concluded the no effect level for this study was 5 mg/kg
b.w./day (Goldenthal, 1980c).
Subsequent to the above report the liver histopathology slides
from the study were evaluated by an independent pathologist. Slides
from all study animals were evaluated. The following
fenbendazole-related changes were reported for the treatment groups:
hepatocellular hypertrophy, vacuolation and bile duct proliferation
in the 15, 45, and 135 mg/kg b.w./day groups, hepatocellular
hyperplasia and biliary cysts in the 45 and 135 mg/kg b.w./day
groups, and hepatocellular adenomas and carcinomas in the 135 mg/kg
b.w./day group. A low incidence of hepatic tumours was noted in this
study including in controls. No treatment-related changes were
reported for the 5 mg/kg b.w./day group (Brown, 1982).
Some differences in criteria and terminology were noted between
the original and review pathologists. Additionally the review
pathologist reviewed only the liver slides. Therefore a consensus
report of hepatic lesions was generated as shown in Table 2:
Table 2: Results of consensus report on hepatic lesions
Dose (mg/kg b.w./d Fenbendazole)
Liver lesions 0 5 15 45 135 Historical
(%) control
Periportal M 0 2 12* 22* 28*
hypertrophy F 1 1 8* 25* 21*
Centrilobular M 0 0 1 2 13*
hypertrophy F 0 0 1 0 5
Diffuse M 0 0 1 6* 6*
hypertrophy F 0 0 0 3 4
Focal vacuolation M 1 2 1 8* 8*
F 4 1 3 0 2
Periportal M 5 7 12 9 6
vacuolation F 4 8 9 14* 14*
Bile duct M 8 7 12 11 7 3-52
proliferation F 7 8 7 21* 26* 1.6-27
Biliary cysts M 1 1 0 6 8*
F 1 3 1 12* 29*
Cholangiosclerosis M 3 2 3 0 0
F 1 3 1 12* 29*
Nodular/focal M 4 6 7 11 13* 0-15
hyperplasia F 11 8 3 14 19 0-18
Neoplastic nodule M 0 2 1 1 3 0-5.7
F 2 0 2 0 3 0-5.7
Adenomas M 0 0 0 1 1 0-3.3
F 1 0 0 0 0 0-2.9
Carcinomas M 1 1 3 0 2 0-5
F 0 0 0 1 3 0-0.8
* Statistically significant compared to concurrent controls.
Note: Group sizes were 50 apart from 49 in high dose male group.
Historical controls from 10 studies were provided, which had a
combined incidence of 1 hepatic carcinoma in 980 female rats while
the present study contained 1 hepatic carcinoma in the 45 mg/kg
b.w./day group and 3 hepatic carcinomas in the 135 mg/kg b.w./day
group females (Muser & McClain, 1982).
Subsequent to this a pathology working group (PWG) was convened
to evaluate the liver histopathology slides from the fenbendazole
chronic rat study. The PWG comprised a chair and 5 additional
independent pathologists. Prior to the PWG the chair reviewed all
liver slides in a blind fashion and issued a report. For the PWG
review the original pathologist's (OP) and the consensus diagnoses
between the original pathologist and review pathologist (RP) when
appropriate had to be matched with the PWG chair's diagnoses. All
hepatocellular neoplasms, all slides showing nodular hyperplasia,
nodular hypertrophy, or neoplastic nodule diagnosed by the OP or RP
and focal hyperplasia diagnosed by the chair, and all slides showing
biliary cyst/cholangioma were reviewed by the PWG and reported as
shown in Table 3:
Table 3. Results of PWG report
Treatment Group (male/female)
Cont 5 15 45 135
Nonneoplastic changes
Focal hyperplasia 3/6 4/4 1/3 1/9 5/16
Foci of cellular 22/24 28/26 29/23 43/29 43/44
alteration
Neoplastic changes
Hepatocellular adenoma 0/1 0/0 0/0 1/1 2/2
Hepatocellular carcinoma 1/0 1/0 3/0 0/1 3/2
Combined neoplasms 1/0 1/0 3/0 1/1 5/4
Hepatocellular hypertrophy 0/2 2/6 17/20 38/40 42/48
Cholangioma 1/0 0/1 0/0 1/3 2/10
Biliary cysts 0/0 1/1 1/0 2/6 3/12
Note: Group sizes as in previous table.
The conclusions of the PWG were:
1. Lifetime treatment of CD rats with fenbendazole in the diet did
not result in a significant compound-related increase in
hepatocellular neoplasms. Differences in incidences among groups
were considered to reflect normal biological variation.
2. Lifetime treatment of CD rats with fenbendazole in the diet was
associated with a significant increase in hepatocellular foci of
cellular alteration at dose levels of 45 and 135 mg/kg b.w./day in
males and 135 mg/kg b.w./day in females. There was also an increase
in hepatocellular focal hyperplasia in females at 135 mg/kg
b.w./day. Foci of cellular alteration and focal hyperplasia were
considered to be toxic lesions that were not associated with
induction of hepatocellular neoplasms in this study.
3. Lifetime treatment of CD rats with fenbendazole in the diet was
associated with a compound-related increase in hepatocellular
hypertrophy at dose levels of 15, 45, and 135 mg/kg b.w./day. It is
interpreted as a common adaptive response to toxicity unrelated to
the formation of hepatic neoplasms.
4. Lifetime treatment of CD rats with fenbendazole in the diet was
associated with a compound-related increase in "cholangiomas" in
females at the 135 mg/kg b.w./day dose level. The incidence of
biliary cysts was also increased in females at both 45 and 135 mg/kg
b.w./day. Biliary cysts and "cholangiomas" were slightly increased
in males at 135 mg/kg b.w./day. The weight of all of the evidence
permitted the consensus opinion of the PWG that the
"cholangioma"/biliary cysts observed in this study represent a toxic
proliferative lesion probably initiated in utero by administration
of excessively high doses of fenbendazole.
There was a reduction in the incidence of hepatocellular
carcinoma in female rats in the 135 mg/kg b.w./day group (2 vs 3)
reported by the PWG compared with the previous consensus report,
although this incidence is still high when compared to historical
controls (Sauer, 1986).
2.2.4 Reproduction studies
2.2.4.1 Rats
The potential reproductive effects of fenbendazole were studied
in a 3-generation reproduction study in Charles River CD rats in
which fenbendazole was administered in the diet to provide doses of
0, 160, 400, and 1000 mg/kg b.w./day. Eighty male and 160 female
rats (weighing 63 to 114 g) were evenly distributed among the
treatment groups. Except during mating the rats were individually
housed in wire-mesh cages. After 70 days of treatment, at
approximately 100 days of age, the F0 parental rats were housed 2
females/male within the same treatment group for 15 days to produce
the F1 generation. The females were examined daily and presence of
sperm or vaginal plug was designated day 0 of pregnancy. Females
were separated and allowed to deliver, with this date designated day
0 of lactation. The pups were counted, sexed and weighed at
designated intervals during lactation. At 21 days pups from the
F1a litters were selected to comprise a 2-year oral toxicity study
in rats. After weaning, the F0 parental rats were reduced to 10
males and 20 females per group and after a 10-day rest period, the
surviving F0 parental rats were mated a second time to produce the
F1b litters. The F1b litters were raised and evaluated in the
same manner as the F1a litters. After weaning the F1b litters
were allowed to remain together for 1 week and then 10 males and 20
females were selected to comprise the F1 generation. After
weaning, any F1b pups not selected for the next generation were
discarded. Five male and 5 female F0 rats per group were
sacrificed and necropsied and the remainder discarded.
Due to signs of toxicity observed at 15 weeks in the F1a
generation rats being used in a 2-year study, the reproductive
toxicology study was terminated after 30 weeks. The F1 rats were
examined externally, sacrificed and discarded. A reduction in weight
gains was consistently seen in treated groups. In general this
effect was more severe in the higher dose groups. Other parameters
were less consistently affected (Goldenthal, 1979b).
The potential reproductive effects of fenbendazole were studied
in a second 3-generation reproduction study in Charles River CD
rats. Fenbendazole was administered in the diet at levels designed
to provide doses of 0, 5, 15, 45, and 135 mg/kg b.w./day. Fresh
diets containing appropriate fenbendazole concentrations were
prepared weekly throughout the study. Diet samples were collected at
study initiation, 3 months, 1 year, and at study termination.
Three-hundred rats were initially distributed among the five
treatment groups to provide 20 males and 40 females per group. Rats
were individually housed except during mating and lactation.
Rats were maintained on their respective diets throughout the
duration of each generation. After 70 days of treatment, at about
100 days of age, the F0 parental rats were mated (2 females/male)
to produce the F1a litters. Rats were maintained together for 15
days and females were checked daily for sperm. This finding was
designated day 0 of pregnancy and females were then placed in
separate cages during gestation. The day of delivery was designated
lactation day 0, and litter size, live and dead pups were
determined. Dams and pups were observed daily and litters were
evaluated on days 1, 4, 7, 14, and 21. Due to decreased body
weights, pups were allowed to remain with dams for an additional
week before weaning. The F1a pups were then utilized for a
life-time carcinogenicity study. After weaning the F0 females and
males were reduced to 20 and 10 animals per treatment group, rested
for 10 days and then mated a second time to produce the F1b
litters.
An identical procedure to that used to produce the F1a
litters was used for the F1b litters, except that females were
housed with different males within the treatment group. After
weaning the F1b pups were maintained together for 1 week, and then
10 males and 20 females were randomly selected from each group to
become the F1 parents. The remaining F1b pups were examined and
sacrificed. Following weaning 5 male and 5 female F0 parents were
sacrificed and received a complete gross necropsy including
determination of organ weights. The following organs from the
control and 135 mg/kg groups were also evaluated
histopathologically: thyroid, heart, lung, stomach, kidneys, spleen,
adrenals, urinary bladder, and gonads. Livers from all dose groups
were evaluated. At approximately 100 days of age, the F1 parental
rats were mated to produce the F2a litters. The F2a litters were
handled in the same manner as the F1a litters, except that at
weaning they were examined for abnormalities, sacrificed and
discarded rather than being used for a chronic study. The F2b
litter and subsequent F2 parental rats and F3a and F3b litters
were produced and evaluated in the same manner. The rats were
observed daily and examined weekly and weights and feed consumption
were recorded on a weekly basis. Observations for the reproductive
aspects of this study included male and female fertility, length of
gestation period, litter size and weight at various stages of
lactation, and pup weight at weaning. All pups dying during
lactation were examined by necropsy or skeletal staining.
A summary of observations reported for the 45 and 135 mg/kg
b.w./day parental rats at various times throughout the study
includes: soft stool with diarrhoea and red discharge, reddening and
yellowish staining of the anal-genital region and emaciation,
reduced weight gains and food consumption, and slight to moderate
histopathologic hepatic changes including hepatocellular
hypertrophy, biliary hyperplasia, and lymphoid cell infiltration.
These changes were more severe for the 135 mg/kg b.w./day group.
Alterations in the 5 and 15 mg/kg b.w./day groups were marginal or
inconsistent when compared to controls. A summary of observations on
reproductive or pup effects of fenbendazole reported for the 135 and
45 mg/kg b.w./day groups at various times throughout the study
includes: reduced fertility indices, survival indices, pup weight,
and lactational growth, as well as diarrhoea, yellow color, reduced
activity, bloated stomach, and alopecia. These effects were also
more pronounced in the high-dose group. Alterations in the 5 and 15
mg/kg b.w./day groups were marginal or inconsistent when compared to
controls. Based on these results the investigators concluded that
the NOEL for this study was 15 mg/kg b.w./day for maternal and
reproductive toxicity (Goldenthal, 1980a).
2.2.5 Special studies on embryotoxicity and/or teratogenicity
2.2.5.1 Rats
The potential embryotoxicity of fenbendazole was evaluated in
Wistar rats. Sexually mature virgin female Wistar rats were mated
with fertile males, to provide 4 groups of 20 pregnant animals. Dams
were evaluated for presence of sperm and the day on which sperm was
detected was designated gestation day one. Dams in these groups
received doses of 0, 25, 250, or 2500 mg/kg b.w./day fenbendazole
via stomach tube in a 2% starch mucilage vehicle at the rate of
10 ml/kg b.w./day on gestation days 7-16. Rats were observed daily,
and weighed weekly. Doses were based on the most recent body weight.
Food intake was monitored continuously. All dams were sacrificed on
gestation day 21 and fetuses were delivered by caesarean section.
Each dam received a gross necropsy and organs were weighed. The
uterus was opened and number and placement of live and dead fetuses
and resorptions were determined. The fetuses were examined
externally for abnormalities; about 50% were then processed for
Alizarin red staining to evaluate skeletal abnormalities and the
remainder were processed with Bouin's solution for evaluation of
soft tissue abnormalities.
No treatment-related effects were noted in any of the maternal
or fetal parameters. One litter in the high-dose group was comprised
entirely of abnormal pups. Abnormalities included shortened, twisted
tails, fused vertebral centrae, diaphragmatic hernia, and
hydrocephalus. The investigators judged this single litter to be an
anomalous finding as no other treatment group or litter within the
high-dose treatment group demonstrated any treatment-related effect.
Based on results of this study the investigators concluded the NOEL
to be 2500 mg/kg b.w./day (Kramer & Baeder, 1973).
Fenbendazole was administered orally to Sprague-Dawley rats on
days 8 to 15 of gestation. There was no evidence of embryotoxic or
teratogenic effects at either of the doses used - 60 and 120 mg/kg
b.w./day. Similar results were obtained with the 6-hydroxy
derivative; and the sulfone metabolite was also without embryotoxic
or teratogenic effect at the highest dose used (66 mg/kg b.w./day).
The sulfoxide (i.e., oxfendazole) at a dose level of 16 mg/kg
b.w./day caused nearly 80% embryolethality and an increase in the
number of external malformations. At a dose of 2 mg/kg b.w./day
there was 100% embryolethality (Delatour and Lapras, 1979).
Febantel and several of its metabolites were tested for
possible embryotoxicity. The compounds were given to rats, by
gavage, during days 8 to 15 of pregnancy, up to the maximum
tolerated dose. Fenbendazole showed no adverse effect at the highest
dose used - 66 mg/kg b.w./day, but administration of febantel and
its two sulfoxide metabolites (the second being oxfendazole)
produced teratogenic effects (increased incidences of external and
skeletal abnormalities) and embryolethality with no-observed-effect
levels of 22, 23 and 10 mg/kg b.w./day respectively (Delatour
et al., 1981a).
2.2.5.2 Rabbits
The potential embryotoxicity of fenbendazole was studied by
administering fenbendazole to pregnant 5-7 month old yellow silver
rabbits. Eleven to 14 females were employed per dose. Rabbits were
mated twice (at 6-hour intervals) with fertile males. After mating,
rabbits were maintained in metal cages with metal gratings. The
pregnant rabbits were divided into 4 groups of 10 and administered
doses of 0, 10, 25, and 63 mg/kg b.w./day on gestation days 7-19.
The test material was administered as suspension in 2% starch
mucilage with a stomach tube at the rate of 5 ml/kg b.w. The rabbits
were observed daily, and weighed weekly. Food intake was monitored
continuously. Does were sacrificed on gestation day 29, received a
complete gross necropsy, and fetuses were delivered by caesarean
section. The uterus was evaluated for resorptions and fetuses were
examined grossly for abnormalities. The fetuses were subsequently
maintained in an incubator for 24 hours. About 50% of the fetuses
were then processed in Bouin's solution for soft tissue examination,
and 50% using Alizarin red stain for skeletal examination.
One doe in the 63 mg/kg b.w./day group aborted on gestation day
27, while 2 does in this group and one in the 25 mg/kg b.w./day
group were found to have resorbed their litters. An increase in
skeletal anomalies (13th rib) and delayed ossification of cranial
bones occurred in the 63 mg/kg b.w./day group. Based on these
findings the investigators concluded the NOEL for this study was
25 mg/kg b.w./day (Scholz & Baeder, 1973).
2.2.5.3 Dogs
Two groups of 12 bitches received oral doses of 100 mg/kg
b.w./day fenbendazole in capsules on gestation days 14-22 or 22-30.
A similar control group received empty capsules. Each group
contained approximately half nulliparous and half multiparous
bitches. Bitches were observed daily through weaning of pups at 6
weeks. A necropsy was performed on all stillborn pups and pups dying
prior to 42 days. About half the bitches in each group produced
litters. No treatment-related findings were reported (Mehring,
1981).
2.2.5.4 Swine
Eight groups of 10 sows received 3 mg fenbendazole/kg in feed
daily for 3 days during week 1, 2, 3, 4, 7, 10, 13, or 14 of
gestation. Ten sows were treated prior to breeding and an equal
number of controls were used. Fenbendazole had no adverse effect on
sows or litters (Evans, 1980).
A total of 104 sows were treated orally with 500 mg/kg b.w./day
(?) fenbendazole once or occasionally multiple times between
gestation days 8 and 33. The sows were allowed to deliver their
litters. The gestation period, live and dead piglets, and
deformities were determined. Live pigs were radiographed for
skeletal abnormalities. No maternal effects or fetal effects were
reported (Tiefenbach, 1984; Baeder 1988).
2.2.5.5 Sheep
In a series of studies pregnant ewes were treated with oral
doses of fenbendazole in the following manner:
a) A group of 15 ewes received 15 mg/kg b.w. four times
during gestation. The exact days of gestation were
variable.
b) A group of 10 ewes were given a single dose of 50 mg/kg
b.w. 96 hours following servicing.
c) A group of 19 ewes received 15 mg/kg b.w. every 4 weeks
during gestation for a total of 7 doses.
Each experiment showed no effects on lambing and no apparent
abnormalities in the offspring (Wilkins, 1973).
2.2.5.6 Cattle
A group of 27 cows were given oral doses of 50 mg/kg b.w.
fenbendazole on days 12 and 21 of gestation, then at 3 week
intervals until the fifth month, and subsequently at 2-monthly
intervals. Another group of 35 cattle was given 20 mg/kg b.w.
fenbendazole on days 9, 10, 19, 30, 69, 99, 129, 159, and 189 of
gestation. In both experiments calving progressed normally and there
were no apparent abnormalities in the offspring (Muser & Lapras,
1979).
2.2.5.7 Horses
Pregnant mares were given oral doses of fenbendazole at 10 or
25 mg/kg b.w./day in the last trimester of pregnancy. Other mares
were given single oral doses of 5 mg/kg b.w. within 1 to 7 weeks of
foaling. In neither case were there apparent effects on foals (Paul
& Muser, 1981).
2.2.6 Special studies on testicular function
2.2.6.1 Sheep
A group of 4 rams were given a single oral dose of 50 mg/kg
b.w. fenbendazole. Another group of 5 rams were dosed orally with
15 mg/kg b.w. monthly for 4 months. Semen quality was unaffected
either during or following treatment (Wilkins, 1973).
2.2.6.2 Horses
Effects on testicular function in stallions were examined in a
study using a single oral dose of 20 mg/kg b.w. fenbendazole. The
animals were castrated 4, 12, 26, 60, or 72 h after dosing. No
effects were seen on seminal volume, spermatozoa counts and
morphology, testicular size and weight or serum testosterone levels
(Squires et al., 1978).
2.2.7 Special studies on genotoxicity
Table 4. Results of genotoxicity studies
Test Test object Dose or Results Reference
system Concentration
Ames test1 S.typhimurium 1-2500 µg Negative Mourot, 1990
TA97, 98, 100,
102
Ames test1 S.typhimurium 1-5000 mg Negative Mazza et al.,
TA98, 100, 1981
1535, 1537,
1538
Ames test1 S.typhimurium 1-10000 Negative Rabenold &
TA1435, 1537 µg/plate Brusick, 1982
Mitotic HeLa cells 1 mg/ml Positive Puenter, 1978
index
Forward Mouse up to 62.25 Weakly Cifone &
mutation1 lymphoma µg/ml positive2 Myrh, 1983a
assay
DNA Primary rat 0.5-100 Negative Myrh &
repair1 hepatocytes µg/ml Brusick, 1982a
Micronucleus Mouse RBCs 3000 mg/kg Negative Horstmann et
test al., 1986
Cytogenetics Chinese 1000-4000 Negative Muller et al.,
assay hamster mg/kg 1986
marrow bone
1. Both with and without rat liver S9.
2. Positive in the presence, but not in the absence of metabolic activation.
2.3 Observations in humans
Five healthy male subjects were given oral doses of 300 mg
fenbendazole with breakfast, and 6 healthy male subjects were given
600 mg fenbendazole 12 hours after their last meals. Serum
concentrations were monitored. The following parameters were
evaluated: Blood pressure, pulse rate, symptom list and self-rating
scale, and clinical chemistry values. Serum values were detected in
2/5 subjects receiving fenbendazole with a meal and 0/6 subjects
receiving fenbendazole without food. No relevant changes were
established in the subjects (Rupp & Hajdu, 1974).
3. COMMENTS
Comprehensive toxicological data on fenbendazole were provided,
including the results of studies on its kinetics, metabolism, short-
and long-term toxicity, carcinogenicity, genotoxicity, reproductive
toxicity, embryotoxicity, and teratogenicity.
The rate of absorption following oral administration was slow,
but more rapid in monogastric animals. The extent of absorption was
25-50% in rats, less than 20% in dogs, 70% in rabbits, 25% in sheep,
and more than 33% in pigs. Elimination was greater than 90% within 3
days, with the majority in the faeces. Fenbendazole was metabolized
to oxfendazole (the sulfoxide), oxfendazole sulfone, and amine
metabolites, which were detectable in plasma. The major urinary
metabolite was 4-hydroxy-fenbendazole, with traces of oxfendazole
and oxfendazole sulfone. The metabolic pathway was similar in rats,
rabbits, dogs, sheep, cattle, goats, and chickens.
In a 24-month study in mice in which fenbendazole was given in
the diet, there were sporadic body-weight differences between
treated and control groups but no meaningful relationship with drug
treatment. Survival was reduced in the treated groups, but only at
the highest dose of 405 mg/kg b.w./day could it be attributed to
fenbendazole administration. There were no increases in tumour
incidence. The NOEL was 135 mg/kg b.w./day.
Rats born during a multigeneration study received fenbendazole
in the diet for 123 weeks at doses of 5, 15, 45, and 135 mg/kg
b.w./day. Diarrhoea was observed at 45 and 135 mg/kg b.w./day;
weight gain was reduced at these doses and in females at 5 mg/kg
b.w./day. Lymph nodes were affected at all but the low dose of
5 mg/kg b.w./day, showing enlargement or cyst formation, sinus
dilatation and reactive hyperplasia. The incidence of testicular
interstitial-cell adenomas was increased in males at the dose level
of 135 mg/kg b.w./day. The major target organ was the liver, which
was affected at and above 15 mg/kg b.w./day. The following
alterations were noted: increased serum alkaline phosphatase
activity, hepatocellular hypertrophy and hyperplasia, bile duct
proliferation and biliary cysts, and cytoplasmic vacuolation. There
was a slight increase in the incidence of hepatocellular carcinomas
in females at 135 mg/kg b.w./day.
The Committee noted that the liver histopathology slides from
the chronic toxicity study in rats had been assessed three times
and, although there were some differences in criteria and
terminology, a consensus had been reached. The incidence of
hepatocellular carcinomas was very low, and there was no
statistically significant increase as compared with controls.
Nevertheless, given the extremely low incidence in concurrent and
historical controls, tumours found in females receiving the highest
dose of fenbendazole may have been related to treatment. It was
noted that the small increase in carcinomas was observed against a
background of statistically significant focal hyperplasia. The NOEL
in this study was found to be 5 mg/kg b.w./day, based on
pathological changes in the liver and lesions in the lymph nodes.
In a series of studies in dogs, fenbendazole was administered
in capsules for periods of 6 days to 6 months. The major toxic
effect was lymphoid hyperplasia in the gastric mucosa and mesenteric
lymph nodes, resulting in an overall NOEL of 4 mg/kg b.w./day. This
effect was considered by the Committee less important than the
changes seen in the liver of rats.
A three-generation reproduction study was conducted in rats
given fenbendazole in the diet at doses of 5, 15, 45, and 135 mg/kg
b.w./day. Toxic effects in adult animals including diarrhoea,
reduced weight gain, and pathological changes in the liver, were
observed at and above 45 mg/kg b.w./day. At these doses there were
also reductions in fertility, survival, and growth of neonates
during lactation. The NOEL was 15 mg/kg b.w./day.
Fenbendazole was tested for embryotoxicity and teratogenicity
in rats and rabbits dosed by gavage. Embryotoxicity was not seen in
either species, while fetotoxicity in the form of an increased
frequency of occurrence of 13th ribs and delayed ossification of
cranial bones occurred in rabbits given a dose of 63 mg/kg b.w./day.
The NOEL were 2500 mg/kg b.w./day in rats and 25 mg/kg b.w./day in
rabbits.
In dogs, pigs, sheep, and cattle, the oral administration of
fenbendazole at various times during the gestation period did not
result in treatment-related effects in the offspring.
Fenbendazole did not produce mutations in bacteria or
chromosomal aberrations in two different in vivo tests. It
increased the mitotic index of HeLa cells in vitro, an effect that
could be related to the ability of benzimidazoles to interfere with
tubulin polymerization and thus inhibit spindle formation.
4. EVALUATION
The most significant toxicological findings with fenbendazole
were in the rat liver. Since fenbendazole appears to be
nongenotoxic, the Committee considered that a threshold would exist
for these effects. Thus a NOEL was based on the absence of
histopathological changes in the liver at 5 mg/kg b.w./day in the
long-term toxicity/carcinogenicity study in rats.
A temporary ADI of 0-25 µg/kg b.w. was established based on the
NOEL of 5 mg/kg b.w./day and the application of a safety factor of
200.
Even though a temporary ADI was established, it was not used
for recommending MRLs. Before the toxicological issues relating to
this compound can be resolved, additional information is required to
explain the mechanism of the observed increased incidence of tumours
in female rats at high doses, including the results of a study of
in vivo DNA binding in the rat liver following oral administration
of fenbendazole (see Summary section on the benzimadozoles).
5. REFERENCES
BAEDER (1988) Teratogenicity study of fenbendazole in sows (German
porker) when administered orally in the feed. Hoechst-Roussel
unpublished report. Submitted to WHO by Hoechst AG, Frankfurt am
Main, Germany.
BOOZE, T.F. & OEHME, F.W. (1983) Safety evaluation of fenbendazole
in swine. Amer J. Vet. Res., 44, 1117-19.
BROWN, W.R. (1982) Lifetime oral toxicity study of fenbendazole in
rats histopathology - liver. Research Pathology Services Inc., New
Britain, Penna. USA unpublished report. Submitted to WHO by Hoechst
AG, Frankfurt am Main, Germany.
CIFONE M.A. & MYHR B.C. (1983) Mutagenicity evaluation of BAY L 5156
in the mouse lymphoma forward mutation assay. Unpublished project
No. 10989 from Litton Bionetics Inc., Kensington, MD, USA. Submitted
to WHO by Bayer AG, Leverkusen, Germany.
DELATOUR, P. & LAPRAS, M. (1979) Comparative embryotoxicity of
fenbendazole and its metabolites. Collection Med. Leg. Toxicol.
Médicale, 111, 143.
DELATOUR. P., DANDON, M., GARNIER, F. & BENOIT, E. (1982a)
Metabolism - embryotoxicity relationship of febantel in the rat and
sheep. Ann. Rech. Vet., 13, 163-170.
DELATOUR, P. & PARISH, R. (1986) Benzimidazole anthelmintics and
related compounds: Toxicity and evaluation of residues. In: Rico, A.
(ed) Drug Residues in Animals, Academic Press, Inc. Orlando,
Florida, pp. 175-204.
DOERR, B., & CARMINES, E. (1983) Final report on 14-week oral
toxicity study of fenbendazole in dogs. Hoechst-Roussel unpublished
report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
DUA, P. (1981) Pathology review of microslides of stomach and lymph
node sections of dogs. FDA report to Hoechst-Roussel
Pharmaceuticals, Somerville, NJ, USA.
DÜWEL (1974) Report on acute oral toxicity test on pigs.
Hoeschst-Roussel Unpublished report. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
DÜWEL & UIHLEIN (1980) Determination of the serum levels of
fenbendazole and its metabolites in rats, rabbits, and dogs after
oral administration of fenbendazole, Hoechst-Roussel Unpublished
report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
EVANS, L.E. (1980) Reproduction, teratogenicity, and fertility study
in boars treated with fenbendazole. Hoechst-Roussel unpublished
report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
GOLDENTHAL, E.I. (1978) Six-month oral toxicity study in dogs.
Unpublished report, International Research and Development
Corporation, Mattawan, MI, USA. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
GOLDENTHAL, E.I. (1979a) Fifteen-week oral toxicity study in rats.
Unpublished report, International Research and Development
Corporation, Mattawan, MI, USA. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
GOLDENTHAL, E.I. (1979b) Three-generation reproduction study in
rats. Unpublished report, International Research and Development
Corporation, Mattawan, MI, USA. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
GOLDENTHAL, E.I. (1980a) Three-generation reproduction study in
rats. Unpublished report, International Research and Development
Corporation, Mattawan, MI, USA. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
GOLDENTHAL, E.I. (1980b) 24-month oral carcinogenicity study in
mice. Unpublished report, International Research and Development
Corporation, Mattawan, MI, USA. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
GOLDENTHAL, E.I. (1980c) Lifetime oral toxicity study in rats.
Unpublished report, International Research and Development
Corporation, Mattawan, MI, USA. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
HAYES, R.H., OEHME, F.W. & LEIPOLD, H. (1983a) Toxicity
investigation of fenbendazole, an anthelmintic of swine. Amer J.
Vet. Res., 44, 1108-11.
HAYES, R.H., OEHME, F.W. & LEIPOLD, H. (1983b) Safety of
fenbendazole in swine. Amer J. Vet. Res., 44, 1112-16.
HORSTMANN, SCHÜTZ, MAYER & LANGER (1986) An oral mutagenicity study
of fenbendazole in mice. Hoechst-Roussel unpublished report.
Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
KELLNER & CHRIST (1973) Pharmacokinetic studies in sheep, dogs,
rabbits, and rats after administration of HOE 881, Hoechst-Roussel
unpublished report. Submitted to WHO by Hoechst AG, Frankfur am
Main, Germany.
KLÖPFFER, G. (1973) Tests on the metabolism of S71 1881 in sheep,
rabbits, and cattle, Hoechst-Roussel unpublished report. Submitted
to WHO by Hoechst AG, Frankfurt am Main, Germany.
KRAMER & BAEDER (1973) A teratogenicity test of HOE 881 with oral
administration in Wistar rats. Hoechst-Roussel unpublished report.
Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
KRAMER & SCHULTES (1973a) Report on an acute subcutaneous safety
evaluation of HOE 881 in rats. Hoechst-Roussel unpublished report.
Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
KRAMER & SCHULTES (1973b) Report on an acute intraperitoneal safety
evaluation of HOE 881 in rats. Hoechst-Roussel unpublished report.
Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
KRAMER & SCHULTES (1973c) A subchronic safety evaluation following
repeated oral administration (30 days) of HOE 881 in rats.
Hoechst-Roussel unpublished report. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
KRAMER & SCHULTES (1973d) A subchronic safety evaluation following
repeated oral administration (30 days) of HOE 881 in dogs.
Hoechst-Roussel unpublished report. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
KRAMER & SCHULTES (1974a) A subchronic safety evaluation (90 days)
of HOE 881 in rats. Hoechst-Roussel unpublished report. Submitted to
WHO by Hoechst AG, Frankfurt am Main, Germany.
KRAMER & SCHULTES (1974b) A subchronic tolerance trial (90 days)
with HOE 881 in dogs. Hoechst-Roussel unpublished report. Submitted
to WHO by Hoechst AG, Frankfurt am Main, Germany.
KRAMER & SCHULTES (1974c) Report on an acute oral test for the
tolerability of S 732542 in mice. Unpublished report No. 116E/112D
from Hoechst AG. Submitted to WHO by Hoechst AG, Frankfurt am Main,
Germany.
KRAMER & SCHULTES (1974d) Report on an acute oral test for the
tolerability of S 732542 in rats. Unpublished report No. 115E/111D
from Hoechst AG. Submitted to WHO by Hoechst AG, Frankfurt am Main,
Germany.
MAZZA, G., GALIZZI, A., DeCARLI, L. (1981) Microbiologic
determination of the mutagenic activity of the compound.
Hoechst-Roussel unpublished report. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
MEHRING, J.S. (1981) Safety study in pregnant bitches with Panacur
(fenbendazole) granules 22.2%. Laboratory Research Enterprises Inc,
Kalamazoo, MI, USA unpublished Report. Submitted to WHO by Hoechst
AG, Frankfurt am Main, Germany.
MEHRING, J.S. (1982) Panacur (fenbendazole) granules 22.2% and
suspension 10% safety studies in puppies. Laboratory Research
Enterprises Inc, Kalamazoo, MI, USA unpublished Report. Submitted to
WHO by Hoechst AG, Frankfurt am Main, Germany.
MOUROU, D. (1990) Fenbendazole Ames test. Submitted to WHO by Centre
National D'Etudes Vétérinaires et Alimentaires, Fougères, France.
MULLER, JUNG, & WEIGAND (1986) Cytogenetic test on bone marrow cells
of the Chinese hamster - in vivo chromosomal analysis,
Hoechst-Roussel unpublished report. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
MUSER, R.K. & LAPRAS, M. (1979) Safety of fenbendazole use in
cattle. Mod. Vet. Pract., 65, 371.
MUSER, R. & McCLAIN, J. (1982) Fenbendazole suspension 10% - cattle.
Hoechst-Roussel unpublished report. Submitted to WHO by Hoechst AG,
Frankfurt am Main, Germany.
MYRH, B.C. & BRUSICK, D.J. (1982) Evaluation of BAY L 5156 in the
primary rat hepatocyte unscheduled DNA synthesis assay. Unpublished
project No. 20991 from Litton Bionetics Inc. Submitted to WHO by
Bayer AG, Leverkusen, Germany.
PAUL, J.W. & MUSER, R.K. (1981) Use of fenbendazole in horses. Mod.
Vet. Pract., 62, 557.
PUENTER, J. (1978) Comparative studies on the effect of the
anthelmintics fenbendazole and mebendazole on mammalian cell
cultures. Hoechst-Roussel unpublished report. Submitted to WHO by
Hoechst AG, Frankfurt am Main, Germany.
RABENOLD, C. & BRUSICK, D.J. (1982) Mutagenicity evaluation of BAY L
5156 Batch 810030 in the Ames Salmonella/microsome plate test.
Unpublished project No. 20988 from Litton Bionetics Inc. Submitted
to WHO by Bayer AG, Leverkusen, Germany.
RUPP, W. & HAJDU, P. (1974) Investigations into the pharmacokinetics
and tolerability of HOE 881 in healthy subjects, Hoechst-Roussel
unpublished report. Submitted to WHO by Hoechst AG, Frankfurt am
Main, Germany.
SAUER, R.M. (1986) Pathology working group report on fenbendazole in
CD-1 rats, Pathco Inc., Gaithersburg, MD, USA, unpublished report.
Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
SCHOLZ & BAEDER (1973) A teratogenicity test of HOE 881 with oral
administration in yellow-silver rabbits. Hoechst-Roussel unpublished
report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
SCHOLZ & SCHULTES (1973a) Report on an acute oral safety evaluation
of the anthelmintic HOE 881 in mice. Hoechst-Roussel unpublished
report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
SCHOLZ & SCHULTES (1973b) Report on an acute oral safety evaluation
of HOE 881 in rats. Hoechst-Roussel unpublished report. Submitted to
WHO by Hoechst AG, Frankfurt am Main, Germany.
SCHOLZ & SCHULTES (1973c) Report on an exploratory acute oral safety
evaluation of the anthelmintic HOE 881 in rabbits. Hoechst-Roussel
unpublished report. Submitted to WHO by Hoechst AG, Frankfurt am
Main, Germany.
SCHOLZ & SCHULTES (1973d) Report on an acute oral safety evaluation
of HOE 881 in dogs. Hoechst-Roussel unpublished report. Submitted to
WHO by Hoechst AG, Frankfurt am Main, Germany.
SHORT, C.R., BARKER, S.A., FLORY, W. (1988) Comparative drug
metabolism and disposition in minor species. Vet. Hum.
Toxicol., 30 (supp 1), 2-8.
SQUIRES E.L., AMACUR, R.P., PICKETT, B.W., BERNDTSON, W.E.,
SHIDELER, R.K. & VOSS, J.L. (1978) Effect of fenbendazole on
reproductive function in stallions. Theriogenology, 9, 447-455.
TIEFENBACH, B. (1984) Report on teratogenicity testing of 500 mg
fenbendazole per kg body weight in sows (German heavy porkers) when
administered orally in the feed. Hoechst-Roussel unpublished report.
Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
VILLNER, CHRIST & RUPP (1974) Investigations into pharmacokinetics
after the intravenous and oral administration of HOE 881-14C in
rats, rabbits, dogs, sheep, and pigs, Hoechst-Roussel unpublished
report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany.
VOGEL & ALPERMANN (1973) Summary of pharmacology HOE 881 dose range
of 100 to 300 mg/kg, Hoechst-Roussel unpublished report. Submitted
to WHO by Hoechst AG, Frankfurt am Main, Germany.
WAZETER, F.X. & GOLDENTHAL, E.I. (1977) Six-month oral toxicity
study in dogs. International Research and Development Corporation
unpublished report. Submitted to WHO by Hoechst AG, Frankfurt am
Main, Germany.
WILKINS, C.A. (1973) Prufungen von Panacur - Teratological trial.
Unpublished report from Hoechst Research Institute, Malelane,
Republic of South Africa. Submitted to WHO by Hoechst AG, Frankfurt
am Main, Germany.